Endocrine and Skeletal Genetics

Question 1

What are the radiographic findings consistent w a classic non-deforming OI w blue sclerae dx

Answer 1

Wormian bones in skull, codfish vertebrae in adults, thin cortices (in extremities), osteopenia

Question 2

What are the radiographic findings consistent w perinatal lethal OI

Answer 2

undermineralization, plaques of calcification in skull, platyspondyly (reduced space between the vertebral bodies in the spine), severely deformed extremities; broad, crumpled, bent femurs; small beaded ribs (pathognomonic)

Question 3

What are the radiographic findings consistent w progressively deforming OI

Answer 3

Wormian bones in skull, codfish vertebrae and kyphoscoliosis, flared metaphyses (popcorn like appearance in childhood), bowing, thin cortices; thin ribs, severe osteoporosis

Question 4

What are the radiographic findings consistent w common variable OI w normal sclerae

Answer 4

With or without Wormian bones in the skull; codfish vertebrae, thin cortices, protrusio acetabuli (displacement of the hip bone)

Question 5

How is the dx of OI established? What type of testing is needed

Answer 5

heterozygous PV in COL1A1 (70%) or COL1A2 (30%)
concurrent gene testing (sequence analysis of both genes followed by del dup if no PV is identified)

Question 6

What are the general features across all types of OI

Answer 6

classified into four types based on clinical presentation, radiographic features, FH, and natural hx
triangular face; scoliosis, early onset arthritis, non-inflammatory arthralgia, myofascial pain; easy bruising, mixed conductive and SNHL afflicts the majority of adults with OI, progressive postpubertal hearing loss is more typical, cognition is expected, gross motor development may be hindered

Question 7

What are the clinical features associated w classic non-deforming OI w blue sclerae (OI type I)

Answer 7

blue sclerae, normal stature
femoral bowing at birth, fractures at birth or with diapering; fractures at a rate of a few to several per year and then decrease in frequency after puberty (usually heal normally w no deformity)
joint hypermobility, degenerative joint dz, dentinogenesis imperfecta, progressive hearing loss in ~50%

Question 8

What are the clinical features associated w perinatal lethal OI (OI type II)

Answer 8

weight and length small for GA, sclerae are dark blue, connective tissue is extremely fragile, skull is large for the body size, extremities are short and bowed, hips are in a “frog leg” position
infants die in the immediate perinatal period; 60% die on the first day, 80% die within the first week; death usually results from pulmonary insufficiency related to the small thorax, rib fractures, or flail chest bc of unstable ribs

Question 9

What are the clinical features associated w progressively deforming OI (OI type III)

Answer 9

apparent at birth; fractures in the newborn period, simply w handling the infant, # and severity of rib fractures lead to death from pulmonary failure in the first few weeks or months of life
most do not walk without assistance, severe bone fragility and marked bone deformity (have as many as 200 fractures and progressive deformity), growth is extremely delayed among the shortest individuals known
intellect is normal unless there have been intracerebral hemorrhages (extremely rare)
considerable heterogeneity is observed at the clinical level, relative macrocephaly and barrel chest deformity; hearing loss generally begins in the teenage yrs; basilar impression (direct mechanical blockage of normal CSF flow) causing posterior skull pain, C2 sensory deficit, tingling in the fourth and fifth digits, and numbness in the medial forearm; Lhermitte’s sign

Question 10

What are the clinical features associated w common variable OI w normal sclerae (OI type IV)

Answer 10

mild short stature, dentinogenesis, adult onset hearing loss, normal to gray sclerae, basilar impression can occur

Question 11

What is the life expectancy of pts w each type of OI

Answer 11

The severely affected neonates with perinatally lethal OI typically do not survive, with a significant proportion of infants dying within the first 48 hours. Aggressive life support can prolong survival but ultimately the most severe forms remain perinatally lethal.
Life expectancy for classic non-deforming OI and common variable OI is normal.
Progressively deforming OI is highly variable and life expectancy may be shortened by the presence of severe kyphoscoliosis with attendant restrictive pulmonary disease resulting in cardiac insufficiency.

Question 12

What is the somatic mosaicism seen in OI

Answer 12

for dominant PVs has been recognized in perinatally lethal OI, progressively deforming OI, and common variable OI
16% of families; somatic mosaicism for variants that result in lethal OI can produce a mild OI phenotype

Question 13

How would you differentiate between non-accidental trauma and OI

Answer 13

continued occurrence of fractures in a child who has been removed from a possibly abusive situation lends support to the possibility of COL1A1/2 OI
metaphyseal and rib fractures, thought to be virtually pathognomonic for child abuse, can rarely occur in OI; blue sclerae are often found in unaffected normal infants until about 18mo
lab testing usually is not needed to differentiate COL1A1/2 OI from non-accidental child abuse and, in some cases, the time required to perform such testing can delay proper disposition of child abuse cases

Question 14

What tx is recommended for OI

Answer 14

bracing to try to stabilize progressively deforming limbs; use of internal robs or braces to stabilize deforming limbs in the milder subtypes; orthotics
mobility devices; fractures tx as the would in unaffected children and adults (period of immobility should be shortened as much as is practical)
screen for basilar impression so that timely surgical intervention can be planned; dental restorations; sx repair of the middle-ear bones, later hearing loss is tx w cochlear implantation

it is appropriate to offer parents the option of allowing the infant to expire without attempting heroic interventions such as assisted ventilation for lethal OI

Question 15

What is the de novo rate for those w mild OI? progressively deforming/perinatal lethal OI?

Answer 15

mild- 60%; severe- 100%

overall rate of parental mosaicism is up to 16% in families with dominant COL1A1 or COL1A2 PVs

Question 16

When can OI be detected prenatally when it is the perinatal lethal form? progressively deforming form?

Answer 16

Perinatally lethal OI. The bony abnormalities can first be seen by ultrasound examination by about 13 to 14 weeks’ gestation. By 16 weeks, femoral length is typically two or more weeks delayed, calvarial mineralization is essentially absent, and ribs generally have identified fractures.

Progressively deforming OI. Limb length generally begins to fall below the growth curve at about 17 to 18 weeks’ gestation; serial ultrasound examinations are required to confirm the trend.

Question 17

What u/s signs may be indicative of OI prenatally?

Answer 17

reduced echogenicity of fetal bones, bowed, crumpled femurs, beaded ribs, evidence of fractures, and markedly diminished calvarial mineralization

Question 18

What is the molecular pathogenesis of OI

Answer 18

COL1A1/2 encode alpha 1 and 2 chains of collagen type 1, forming most connective tissues and abundant in bone, cornea, dermis, and tendon
Gly-X-Y triplet, glycine must be in the third position to allow proper chain folding to occur

Question 19

What are the disease mechanisms seen in OI

Answer 19

Quantitative changes, which lead to loss of function, tend to have a milder phenotype when compared to qualitative changes, which impart a dominant-negative effect.

Classic non-deforming OI (quantitative, loss of function):
Decreased production of structurally normal type I procollagen results in a reduction in the amount of bone that can be made, leading to brittle bones.
The vast majority of disease-causing variants are premature termination codons (e.g., frameshift, nonsense, splice site variants) that result in the reduction of COL1A1 mRNA by half.

Perinatally lethal OI, progressively deforming OI, and common variable OI (qualitative, gain of function):
Substitutions for glycine resulting in additional post-translation modification that prevents secretion of the assembled trimers.
Small in-frame deletions or duplications of single amino acids or Gly-X-Y triplets and exon-skipping events may disrupt trimer assembly.
Diminished amount of type I procollagen is secreted.
Clinical consequence is influenced by the position of the substituted glycine, the chain in which the substitution occurs, and the nature of the substituting amino acid.
Pathogenic variants closer to the 5’ end of the protein are likely to result in milder clinical phenotypes

Question 20

How is the dx of achondroplasia established

Answer 20

can be established on the basis of clinical and radiographic features
those w typical findings generally do not need molecular confirmation of the dx, although confirmation may aid in receiving new txs

Question 21

What molecular testing should be used for dx of achondroplasia

Answer 21

targeted analysis for two common PVs: p.Gly380Arg (c.1138G>A, c.1138G>C) which are GOF
can also do a multigene panel

Question 22

What are the clinical features associated w achondroplasia

Answer 22

short stature caused by rhizomelic shortening of the limbs, macrocephaly, characteristic facies (Frontal bossing and midface retrusion), exaggerated lumbar lordosis, limitation of elbow extension and rotation, genu varum (knock knees), brachydactyly, and trident appearance of the hands. Excess mobility of the knees, hips, and most other joints is common

obesity is a major problem, can aggravate the morbidity associated w lumbar stenosis
mild to moderate hypotonia, difficulty in supporting their heads bc of both hypotonia and large head size; snowplowing (using head and feet to leverage movement); conductive hearing loss (40%)

some infants die in the first yr of life from complications related to the craniocervical junction; small chest w smaller lung volumes and restrictive pulmonary dz; obstructive sleep apnea

bowing of the lower legs, kyphosis in 90-95%; spinal stenosis, joint laxity in childhood (most joints are hypermobile)

Question 23

What is the prognosis of achondroplasia

Answer 23

life expectancy appeared to be decreased by ~10yrs

Question 24

What are the tx’s for achondroplasia

Answer 24

hydrocephalus: referral to a neurosurgeon; if there is a clear indication of symptomatic compression, urgent referral to a pediatric neurosurgeon for decompression sx should be initiated
obstructive sleep apnea: adenotonsillectomy, positive airway pressure, trach (rare, extreme), weight reduction
middle ear dysfunction: aggressive management of frequent middle ear infections, long-lasting tubes
varus deformity: orthopedic sx
kyphosis: improves significantly or resolves in the majority of children, bracing is usually sufficient, spinal sx may be necessary
spinal stenosis: urgent sx referral is appropriate
adaptive needs: due to short stature, environmental modifications are necessary; most children should have a 504 plan

Question 25

What should pts w achondroplasia avoid

Answer 25

remain rear-facing in car seats as long as possible; avoid soft-back infant seats w increase likelihood to develop kyphosis; limit risk of injury to the spinal cord
no increased risks for bone fragility or joint degeneration in these individuals

Question 26

What is the de novo rate for achondroplasia? What else is it associated w?

Answer 26

80%
associated w APA; de novo PVs are exclusively inherited from the father

Question 27

What is the molecular pathogenesis of achondroplasia

Answer 27

Fibroblast growth factor (FGFR3)
p.Gly380Arg PV causes constitutive activation of FGFR3, which is, through its inhibition of chondrocyte proliferation, a negative regulator of bone growth

Question 28

What are the clinical features associated w hypochondroplasia

Answer 28

skeletal dysplasia
short stature, stocky build, disproportionately short arms and legs; broad, short hands and feet; mild joint laxity; and macrocephaly
skeletal features are very similar to those seen in achondroplasia but tend to be milder. Medical complications common to achondroplasia (e.g., spinal stenosis, tibial bowing, obstructive apnea) occur less frequently in hypochondroplasia but intellectual disability and epilepsy may be more prevalent.
present as toddlers or at early school age with decreased growth velocity leading to short stature and limb disproportion. Other features also become more prominent over time.

birth weight and length are normal range (unlike achondroplasia)
exaggerated lumbar lordosis and mild genu varum; hands are relatively short but do not exhibit the “trident” appearance that is typical in achondroplasia; unlike achondroplasia, motor milestones are NOT significantly delayed

Question 29

How is the dx of hypochondroplasia established

Answer 29

established in a proband w characteristic clinical and radiographic features
Identification of a heterozygous FGFR3 pathogenic variant known to be associated with hypochondroplasia can confirm the diagnosis and help distinguish hypochondroplasia from achondroplasia and other related skeletal dysplasias

like some forms of achondroplasia, GOF mechanism

Question 30

What is the recommended tx for pts w hypochondroplasia

Answer 30

Management of short stature in hypochondroplasia is influenced by parental expectations and concerns; one approach is to address these concerns rather than trying to treat the child. Suboccipital decompression if neurologic status is affected by spinal cord compression. Treatment for thoracolumbar kyphosis and/or genu varum as per orthopedic surgeon if necessary. Laminectomy relieves symptoms of spinal stenosis; about 70% of individuals experience relief of symptoms following decompression without laminectomy. Epilepsy is treated in the standard fashion. Developmental milestones are followed closely during early childhood so that cognitive impairments are addressed with special educational programs.

Question 31

What pregnancy management is recommended for pts w hypochondroplasia

Answer 31

Vaginal deliveries are possible, although for each pregnancy, pelvic outlet capacity should be assessed in relation to fetal head size; epidural or spinal anesthetic can be used, but a consultation with an anesthesiologist prior to delivery is recommended to assess the spinal anatomy; spinal stenosis may be aggravated during pregnancy.

Question 32

What testing should be ordered for dx of hypochondroplasia

Answer 32

targeted analysis for PVs c.1620C>A and c.1620C>G (p.Asn540Lys) can be performed first followed by sequence analysis of FGFR3
these are the most severe PVs w more severe manifestations

Question 33

What is the de novo rate for hypochondroplasia? What else is it associated w?

Answer 33

Because the skeletal features of hypochondroplasia are milder than those of achondroplasia and the incidence of disabilities is lower, the reproductive fitness of individuals with hypochondroplasia is most likely greater than that of individuals with achondroplasia. It is likely that the number of families with multiple affected members is higher for hypochondroplasia than for achondroplasia, and that the percentage of cases of hypochondroplasia attributable to de novo pathogenic variants is less than the 80% figure stated for achondroplasia.
APA

Question 34

Describe the clinical features associated w campomelic dysplasia

Answer 34

skeletal dysplasia characterized by distinctive facies, Pierre Robin sequence with cleft palate, shortening and bowing of long bones, and clubfeet. Other findings include laryngotracheomalacia with respiratory compromise and ambiguous genitalia or normal female external genitalia in most individuals with a 46,XY karyotype. Many affected infants die in the neonatal period; additional findings identified in long-term survivors include short stature, cervical spine instability with cord compression, progressive scoliosis, and hearing impairment.
11 pairs of ribs
cause of death in CD is not related to thoracic cage hypoplasia but rather to airway instability (tracheobronchomalacia) or cervical spine instability; facies resembles type 2 collagen disorders (Stickler), w Pierre Robin and flat midface
INTELLECT IS NORMAL

Question 35

How is the dx of campomelic dysplasia established

Answer 35

diagnosis of CD is usually based on clinical and radiographic findings. Identification of a heterozygous pathogenic variant in SOX9 by molecular genetic testing can confirm the diagnosis if clinical and radiographic features are inconclusive.
heterozygous interstitial del or reciprocal t of 17q24.3-q25.1

Question 36

What are the tx recommendations for campomelic dysplasia

Answer 36

Care of children with cleft palate by a craniofacial team using routine measures; in persons with a 46,XY karyotype and undermasculinization of the genitalia, the gonads should be removed because of the increased risk for gonadoblastoma; care of hip subluxation and clubfeet using standard protocols; hearing aids for those with hearing impairment; surgery as needed for cervical vertebral instability and progressive cervicothoracic kyphoscoliosis that compromises lung function.

Question 37

What testing should be ordered for dx of campomelic dysplasia

Answer 37

combination of gene-targeted testing for SOX9, chromosomal microarray (for 17q24.3-q25.1 del), karyotype (for 17q24.3-q25.1 translocation), and comprehensive genomic testing
penetrance in SOX9 PVs in coding region; breakpoints at long distance from SOX9 may not be completely penetrant

Question 38

What on prenatal u/s would indicate a dx of campomelic dysplasia

Answer 38

increased NT, micrognathia, short bowed limbs, and hypoplastic scapulae

Question 39

What is the molecular pathogenesis of campomelic dysplasia

Answer 39

PVs within SOX9 coding region leads to an altered SOX9 protein w impaired activity to function as a transcription factor (LOF or dominant negative)
chromosome rearrangements most likely lead to reduced expression of SOX9
SOC9 functions as a testis-determining gene downstream of SRY, inducing the formation of Sertoli cells and production of the AMH (antimullerian hormone)

Question 40

What are the clinical features associated w cleidocranial dysplasia

Answer 40

skeletal dysplasia
classic triad of delayed closure of the cranial sutures, hypoplastic or aplastic clavicles, and dental abnormalities
can also be mild or have isolated dental anomalies without other skeletal features
abnormally large, wide-open fontanelles (metopic suture) at birth that may remain open throughout life; presence of Wormian bones, cone-shaped thorax; osteopenia/osteoporosis. Clavicular hypoplasia can result in narrow, sloping shoulders that can be opposed at the midline. Moderate short stature
dental anomalies, delayed eruption of secondary dentition, failure to shed the primary teeth, and supernumerary teeth

recurrent ear infections leading to conductive hearing loss, and upper airway obstruction. Intelligence is typically normal.

Question 41

How is the dx of cleidocranial dysplasia established

Answer 41

The diagnosis of CCD spectrum disorder is established in an individual with typical clinical and radiographic findings and/or a heterozygous pathogenic variant in RUNX2 identified (LOF)
sequence analysis then del dup
karyotype: someone w features and multiple congenital anomalies can evaluate for complex chromosome rearrangements or translocations that involve 6p21.2 (RUNX2 locus)

Question 42

What is the recommended tx for cleidocranial dysplasia

Answer 42

If the cranial vault defect is significant, the head needs protection from blunt trauma; helmets may be used for high-risk activities. Surgical cosmesis for depressed forehead or lengthening of hypoplastic clavicles can be considered. Careful planning of anesthetic management due to craniofacial and dental abnormalities. Consultation with an otolaryngologist to assist in securing the airway. Consideration of alternative anesthetic approaches, including neuraxial block, taking into account possible spine abnormalities. If bone density is below normal, treatment with calcium and vitamin D supplementation. Dental procedures to address retention of primary dentition, presence of supernumerary teeth, and non-eruption of secondary dentition. Such procedures may include prosthetic replacements, removal of the supernumerary teeth followed by surgical repositioning of the secondary teeth, and a combination of surgical and orthodontic measures for actively erupting and aligning the impacted secondary teeth. Speech therapy as needed. Aggressive treatment of sinus and middle ear infections; consideration of tympanostomy tubes for recurrent middle ear infections; regular immunizations including influenza. Sleep study in those with manifestations of obstructive sleep apnea; surgical intervention may be required for upper airway obstruction.

Question 43

What are the features on u/s that are consistent w a cleidocranial dysplasia dx

Answer 43

as early as 14wks gestation can be seen
abnormal clavicles that are short (<5th percentile) or partially or totally absent
brachycephalic skull w under mineralization, frontal bossing, and generalized immature ossification

Question 44

What are the clinical features associated w MODY

Answer 44

group of inherited disorders of non-autoimmune diabetes mellitus which usually presents in adolescence or young adulthood (accounts for 1-3% of all diabetes)
early onset diabetes, mild stable fasting hyperglycemia, extreme sensitivity to sulfonylureas, extrapancreatic features
absence of pancreatic islet autoantibodies, endogenous insulin production beyond 3-5yrs after onset of diabetes
low insulin requirement for tx, lack of ketoacidosis when insulin is omitted from tx (these are all atypical for type 1 diabetes dx)
onset of diabetes <45yo, lack of significant obesity, normal triglyceride levels (all atypical for type 2 diabetes)

Question 45

What % of PVs contribute to each type of MODY

Answer 45

30-60% caused by GCK-MODY (type 2) and HNF1A (type 3)
10% caused by HNF4A-MODY (type 1) and HNF1B-MODY (type 5)

Question 46

What are the specific features associated w GCK-MODY

Answer 46

mild, stable fasting hyperglycemia present at birth
beta-cell function shows minimal deterioration w increasing age, generally asymptomatic
hyperglycemia is often discovered during routine medical exam
diabetes-related complications are extremely uncommon

Question 47

What are the specific features associated w HNF1A-MODY

Answer 47

associated w onset of diabetes in late adolescence or early adulthood
prior to developing overt diabetes, heterozygotes have marked progressive beta-cell dysfunction, increased insulin sensitivity, and glycosuria
oral glucose tolerance tests show a very large glucose increment, usually >90mg/dl
penetrance is high: 63% develop diabetes by 25yo, 79% by 35yo

Question 48

What are the specific features associated w HNF1B-MODY

Answer 48

renal involvement is more common than diabetes
moat common are renal cysts, which can be evident prenatally as isolated bilateral hyperechogenic kidneys; majority w normal sized or small kidneys w hyperechogenicity and/or renal cysts; absence of a kidney and renal hypoplasia
renal magnesium wasting, life threatening hypomagnesemia, hyperuricemia which can manifest as early onset gout
early onset diabetes is the most common extrarenal manifestation, mean age of onset @24yo; pancreatic atrophy, genital tract abnormalities in females, abnormal liver function, and primary hyperparathyroidism

Question 49

What are the specific features associated w HNF4A-MODY

Answer 49

transient hyperinsulinemic hypoglycemia in the neonatal period, followed later by diabetes in late adolescence or adulthood

Question 50

What lab testing may be consistent w a MODY dx

Answer 50

GCK-MODY: serum glucose and hemoglobin A1c can help w dx bc they fall within the following expected ranges:
fasting serum glucose: typical range 99-104 (normal ~6)
HbA1c: ~6% @40yo or younger, and slightly higher than 6% older than 40yo

Question 51

What testing should be ordered for MODY

Answer 51

serial single gene testing: sequence analysis of the most likely genes first then del dup for the following genes specifically: CEL, GCK, HNF1A, HNF1B, HNF5A
a MODY multigene panel
CMA: in individual w distinguishing phenotypic features suggestive of a contiguous gene del, such as a 17q12 recurrent del syndrome which includes a del that encompasses HNF1B

Question 52

What are the tx options for MODY

Answer 52

GCK MODY in isolation does not require tx/pharmacologic therapy; screen annually for retinopathy in older individuals

HNF1A-MODY. The first-line therapy is low dose sulfonylureas which act downstream of the genetic defect and increase insulin secretion via a glucose-independent mechanism; Because individuals with HNF1A-MODY have normal or even increased insulin sensitivity, sulfonylureas can (even at low doses) cause hypoglycemia, which may limit their use in some patients. In such cases, treatment with meglitinides
increased risk of cardiovascular dz and should be tx w statin therapy by 40yo

HNF1B-MODY: does not show the same sensitivity to sulfonylureas as HNF1A-MODY. Insulin sensitivity to endogenous glucose is decreased even though peripheral insulin sensitivity is normal; insulin therapy is often required

HNF5A-MODY: sulfonylureas are the established first line tx

Question 53

What should be recommended to pregnancies w GCK- MODY

Answer 53

Insulin may be required
Using abdominal circumference measurements obtained on second trimester ultrasound examination, it is assumed that a fetal abdominal circumference >75th centile indicates that the fetus has not inherited the maternal GCK pathogenic variant
If the fetus has inherited the maternal GCK pathogenic variant, the fetus will produce normal amounts of insulin and grow normally. Current recommendations do not support use of insulin in the mother.
If the fetus has not inherited the maternal GCK pathogenic variant, the fetus will respond to maternal hyperglycemia with excess insulin production resulting in excess growth. While current recommendations are to treat the mother with insulin to decrease the risk of macrosomia, data to support these recommendations are limited.
If the fetus inherits a GCK pathogenic variant from the father or has a de novo GCK pathogenic variant, the fetus will have decreased insulin secretion leading to lower birth weight.

Question 54

What should be recommended in pregnancies w HNF1A-MODY

Answer 54

Hyperglycemia during pregnancy in a woman with HNF1A-MODY can be managed with sulfonylureas or insulin and result in normal-size infants

Women who have pre-pregnancy insulin-dependent diabetes are at increased risk of having a child with a birth defect (~6%-8% risk). Women with non-insulin dependent diabetes prior to pregnancy are also at risk greater than the general population of having a baby with a birth defect; however, their risk is less than that of women who have insulin-dependent diabetes prior to pregnancy.

Question 55

What is the purpose of NBS for CAH and what does it identify

Answer 55

1. to identify infants, especially males, w the classic form of 21-OHD CAH who are at risk for life-threatening salt-wasting crises
2. to expedite the dx of females w ambiguous genitalia
   NBS RARELY detects those w the non-classic form

concentration of 17-OHP is measured; majority of screening programs use a single screening test w/out retesting of samples w questionable 17-OHP concentrations

blood taken <24hrs may give false positives, which can also be seen in those w low birth weight or premature infants; false negatives can be seen in infants taking dexamethasone

Question 56

How is the dx of classic CAH established

Answer 56

serum 17-OHP high
Adrenal androgens are elevated; Δ4-androstenedione, 21 deoxycortisol, and progesterone are increased in males and females
Testosterone and adrenal androgen precursors (Δ4androstenedione, DHEA) are increased in affected females and prepubertal males.
Plasma renin activity is markedly elevated in individuals with the salt-wasting form of 21-OHD CAH
Identification of biallelic pathogenic variants in CYP21A2

Question 57

How is the dx of non-classic CAH established

Answer 57

Identification of biallelic pathogenic variants in CYP21A2
60-minute ACTH stimulation test. The serum concentration of 17-OHP
17-hydroxyprogesterone (17-OHP). A single early-morning (<8AM) measurement of plasma 17-OHP concentration

Question 58

Based on 17-OHP levels, what is consistent w the dx of CAH (classic and non-classic)

Answer 58

classic: >10,000ng/dL or 300nmol/L at baseline and after ACTH stimulation
non-classic: 200-10,000ng/dL or 6-300nmol/L at baseline and 1,000-10,000ng/dL or 31-300nmol/L after ACTH stimulation

Question 59

What molecular testing should be ordered for identification of CAH

Answer 59

sequence analysis of CYP21A2 w del dup after; when targeted analysis detects multiple PVs, it is possible that the PVs are either in trans or cis due to a large scale gene conversion w a psuedogene
multigene panel

Question 60

What are the GENERAL features associated w classic CAH

Answer 60

In classic 21-OHD CAH prenatal exposure to potent androgens such as testosterone and Δ4-androstenedione at critical stages of sexual development virilizes the external genitalia of genetic females, often resulting in genital ambiguity at birth. The classic form is further divided into the simple virilizing form (~25% of individuals) and the salt-wasting form, in which aldosterone production is inadequate (≥75% of individuals). Newborns with saltwasting CAH caused by 21-OHD CAH are at risk for life-threatening salt-wasting crises.

Question 61

What are the GENERAL features associated w non-classic CAH

Answer 61

Individuals with the non-classic form of 21-OHD CAH have only moderate enzyme deficiency and present postnatally with signs of hyperandrogenism; females with the non-classic form are not virilized at birth.

Question 62

State whether the following are present/absent/or variable in the classic and nonclassic forms of CAH: prenatal virilization, postnatal virilization, salt wasting, and cortisol deficiency

Answer 62

Classic
prenatal virilization: in females
postnatal virilization: in females and males
salt-wasting: ~75% of all individuals
cortisol deficiency: ~100%
Non-classic
prenatal virilization: absent
postnatal virilization: variable
salt-wasting: absent
cortisol deficiency: rare

Question 63

Describe the clinical features of classic simple virilizing 21-OHD CAH

Answer 63

excess adrenal androgen production: genital virilization at birth in 46,XX females, varying degrees of enlargement of the clitoris, fusion of the labioscrotal folds, and formation of a urogenital sinus; (AMH) is not secreted, the müllerian ducts develop normally into a uterus and fallopian tubes in affected females
After birth, both females and males with classic simple virilizing 21-OHD CAH who do not receive glucocorticoid replacement therapy develop signs of androgen excess including precocious development of pubic and axillary hair, acne, rapid linear growth, and advanced bone age. Untreated males have progressive penile enlargement and small testes. Untreated females have clitoral enlargement, hirsutism, male pattern baldness, menstrual abnormalities, and reduced fertility.
initial growth (if untx) is rapid; potential height is reduced from premature epiphyseal fusion
central precocious puberty may occur when glucocorticoid treatment releases the hypothalamic pituitary axis from inhibition by estrogens derived from excess adrenal androgen secretion.
fertility rates are reported to be low

in males, the main cause of subfertility is the presence of testicular adrenal rest tumors from aberrant adrenal tissue; hypogonadotropic hypogonadism from suppression of LH secretion
deficiency of cortisol also affects the development and functioning of the adrenal medulla causing lower epi and metanephrine concentrations

Question 64

Describe the clinical features associated w classic salt-wasting 21-OHD-CAH

Answer 64

adrenal aldosterone secretion is insufficient for sodium reabsorption by the distal renal tubules
cortisol deficiency and androgen excess.
poor feeding, weight loss, failure to thrive, vomiting, dehydration, hypotension, hyponatremia, and hyperkalemic metabolic acidosis progressing to adrenal crisis (azotemia, vascular collapse, shock, and death). Adrenal crisis can occur as early as age one to four weeks.

affected males not detected by NBS are at high risk bc their normal male genitalia do not alert medical professionals to their condition
some degree of aldosterone deficiency

Question 65

What are the clinical features associated w non-classic CAH

Answer 65

may present at any time postnatally
normal genitalia, hirsutism (60%), frontal baldness, delayed menarche, menstrual irregularities, and infertility
10% have hirsutism and a menstrual disorder, 10% have a menstrual disorder only
PCOS in many affected individuals; fertility rate ~50%
prenatal androgen exposure in females has a virilizing effect on the external genitalia and childhood behavior; more likely to have gender dysphoria, and experience less heterosexual interest and reduced satisfaction with the assignment to the female sex

males: early beard growth and an enlarged phallus with relatively small testes; normal sperm counts, Bilateral adrenocortical incidentoma was reported as the sole finding in an adult male with non-classic CAH

Question 66

What is the pathogenesis of CAH

Answer 66

When the function of 21-hydroxylating cytochrome 450 is inadequate, the cortisol production pathway is blocked, leading to the accumulation of 17-hydroxyprogesterone (17-OHP). The excess 17-OHP is shunted into the intact androgen pathway where the 17,20-lyase enzyme converts the 17-OHP to Δ4androstenedione, which is converted into androgens. Since the mineralocorticoid pathway requires minimal 21hydroxylase activity, mineralocorticoid deficiency (salt wasting) is a feature of the most severe form of the disease.
The lack of steroid product impairs the negative feedback control of adrenocorticotropin (ACTH) secretion from the pituitary, leading to chronic stimulation of the adrenal cortex by ACTH, resulting in adrenal hyperplasia.

Question 67

What are genotype/phenotype correlations seen in CAH

Answer 67

Salt-wasting 21-OHD CAH usually has the most severe pathogenic variants (e.g., homozygous deletions).
Non-classic 21-OHD CAH usually has one mild allele or both mild alleles.
The genotype for the classic form of 21-OHD CAH is predicted to be a severe pathogenic variant on both CYP21A2 alleles, with completely abolished enzyme activity determined by in vitro expression studies.

Individuals with non-classic CAH are predicted to have two mild variants or one mild and one severe variant. Approximately two-thirds of individuals with non-classic 21-OHD CAH are compound heterozygotes. Pathogenic missense variants p.Pro31Leu in exon 1 and p.Val282Leu in exon 7 reduce enzyme activity and are generally associated with this form of the disease.

Question 68

What is the recommended tx for pts w classic CAH

Answer 68

It is imperative to make the diagnosis of 21-OHD CAH as quickly as possible in order to initiate therapy and arrest the effects of cortisol deficiency and mineralocorticoid deficiency, if present.
Glucocorticoid replacement therapy: The goal of glucocorticoid replacement therapy is to replace deficient steroids, minimize adrenal sex hormone and glucocorticoid excess, prevent virilization, optimize growth, and promote fertility (Hydrocortisone in tablet form is the treatment of choice in growing children); During periods of stress (e.g., surgery, febrile illness, shock, major trauma), all individuals with classic 21OHD CAH require increased amounts of glucocorticoids
Mineralocorticoid replacement therapy
Feminizing genitoplasty: Surgery should only be considered in cases of severe virilization (Prader III-V) and be performed in conjunction, when appropriate, with repair of the common urogenital sinus; Emphasis is on functional outcome rather than a strictly cosmetic appearance
Precocious puberty: The true precocious puberty that may occur in 21-OHD CAH can be treated with analogs of luteinizing hormone-releasing hormone (LHRH)
Testicular adrenal rest tumors: Response of testicular adrenal rest tumors to intensified glucocorticoid treatment may decrease the tumor size and improve testicular function
adrenalectomy: Bilateral adrenalectomy has been reported as a treatment of individuals with severe 21-OHD CAH who are homozygous for a null variant and who have a history of poor control with hormone replacement therapy

Question 69

What is the prognosis of those w classic CAH

Answer 69

good prognosis and normal life expectancy
Affected individuals were significantly shorter and had a higher body mass index.
Women with classic CAH had increased diastolic blood pressure.
Metabolic abnormalities were common among studied individuals, and included obesity (41%), hypercholesterolemia (46%), insulin resistance (29%), osteopenia (40%), and osteoporosis (7%). Subjective health status was significantly impaired and fertility compromised.

Question 70

What are the tx recommendations for a pt w non-classic CAH

Answer 70

Individuals with non-classic 21-OHD CAH do not always require treatment. Many are asymptomatic
Traditionally, individuals with non-classic 21-OHD CAH have been treated with lower amounts of glucocorticoid than those required for individuals with classic 21-OHD CAH.

Question 71

What can heterozygotes of CAH have

Answer 71

slightly elevated 17-OHP levels (not enough to use only biochemical testing to determine carrier status, still do molecular testing)

Question 72

Prenatally, what would increase your suspicion for CAH

Answer 72

A 46,XX karyotype in an SRY negative fetus w a normal appearing uterus should raise consideration of classic 21-OHD CAH

Question 73

What is the molecular pathogenesis of CAH

Answer 73

CYP21A2, is located approximately 30 kb from a nonfunctional pseudogene, CYP21A1P, on chromosome 6p in the human leukocyte antigen (HLA) gene cluster.

recombination events are a major cause of CYP21A2 pathogenic variants that result in 21-OHD CAH; high degree of sequence similarity between CYP21A2 and CYP21A1P facilitates gene conversion; a segment of functional CYP21A2 is replaced by a segment copied from the CYP21A1P pseudogene

Approximately 20%-30% of mutated alleles are the result of meiotic recombination between repeated sequences that result in a 30-kb deletion

Question 74

What are the general clinical features associated w Androgen Insensitivity Syndrome? What are the different classifications?

Answer 74

evidence of feminization (i.e., undermasculinization) of the external genitalia at birth, abnormal secondary sexual development in puberty, and infertility (almost always) in individuals with a 46,XY karyotype; impaired development of the prostate and of the wolffian duct derivatives demonstrated by u/s and/or axillary hair
Complete androgen insensitivity syndrome (CAIS), with typical female external genitalia
Partial androgen insensitivity syndrome (PAIS) with predominantly female, predominantly male, or ambiguous external genitalia
Mild androgen insensitivity syndrome (MAIS) with typical male external genitalia

Question 75

How is the dx of androgen insensitivity syndrome established

Answer 75

The diagnosis of AIS is established in an individual with a 46,XY karyotype who has: undermasculinization of the external genitalia, impaired spermatogenesis with otherwise normal testes, absent or rudimentary müllerian structure (fallopian tubes, uterus, cervix, and short vagina), evidence of normal or increased synthesis of testosterone and its normal conversion to dihydrotestosterone, and normal or increased luteinizing hormone (LH) production by the pituitary gland; AND/OR a hemizygous pathogenic variant in AR identified by molecular genetic testing.

Question 76

What are the recommended tx options for pts w androgen insensitivity syndrome

Answer 76

To prevent testicular malignancy, treatment of CAIS may include either removal of the testes after puberty when feminization is complete or prepubertal gonadectomy accompanied by estrogen replacement therapy. Because the risk of malignancy is low, however, removal of gonads is increasingly controversial. Additional treatment for CAIS may include vaginal dilation to avoid dyspareunia. Treatment of PAIS in individuals with predominantly female genitalia is similar to treatment of CAIS, but is more likely to include prepubertal gonadectomy to help avoid increasing clitoromegaly at the time of puberty. In individuals with PAIS and ambiguous or predominantly male genitalia, the tendency has been for parents and health care professionals to assign sex of rearing after an expert evaluation has been completed. Those individuals with PAIS who are raised as males may undergo urologic surgery such as orchiopexy and hypospadias repair. Those individuals with PAIS who are raised as females and who undergo gonadectomy after puberty may need combined estrogen and androgen replacement therapy. Males with MAIS may require mammoplasty for gynecomastia. A trial of androgen pharmacotherapy may help improve virilization in infancy. It is best if the diagnosis of AIS is explained to the affected individual and family in an empathic environment, with both professional and family support.

Question 77

What do heterozygous females of androgen insensitivity syndrome have

Answer 77

10% have asymmetric distribution and sparse or delayed growth of pubic and/or axillary hair

Question 78

Describe an alternate testing if molecular genetic testing fails for a pt w suspected androgen insensitivity syndrome

Answer 78

Androgen binding assay: If molecular genetic testing fails to identify a pathogenic variant that can explain the affected individual’s phenotype, testing of a biopsy of genital skin for defective androgen binding may be considered. As a result of the increasing number of individuals with features of PAIS in whom no pathogenic AR variant is able to be identified, there has been an increase in demand for androgen binding assays to confirm the diagnosis of AIS.

Question 79

What are the features specific to complete androgen insensitivity syndrome

Answer 79

female external genitalia; present either before puberty or at puberty w primary amenorrhea
Absent OR rudimentary wolffian duct derivatives
Absence or presence of epididymides &/or vas deferens
Inguinal, labial, or abdominal testes
Short blind-ending vagina
Scant OR absent pubic &/OR axillary hair
Breast and female adiposity develop normally
Sexual identity and orientation are typically female and heterosexual

Question 80

What are the features specific to partial androgen insensitivity syndrome w predominantly female features

Answer 80

predominantly female genitalia, “incomplete AIS”
Inguinal OR labial testes
Clitoromegaly & labial fusion
Distinct urethral & vaginal openings OR aurogenital sinus

Question 81

What are the features specific to partial androgen insensitivity syndrome w ambiguous features

Answer 81

Microphallus (<1 cm) with clitoris-like underdeveloped glans; labia majora-like bifid scrotum
Descended OR undescended testes
Perineoscrotal hypospadias OR urogenital sinus
Gynecomastia (development of breasts) in puberty
Establishing sex of rearing may be an issue for children w frank genital ambiguity

Question 82

What are the features specific to partial androgen insensitivity syndrome w male features

Answer 82

Simple (glandular or penile) OR severe (perineal) “isolated” hypospadias w/normal-sized penis & descended testes OR severe hypospadias w/micropenis, bifid scrotum, & either descended or undescended testes
Gynecomastia in puberty

Question 83

What are the features specific to mild androgen insensitivity syndrome

Answer 83

Impaired spermatogenesis &/OR impaired pubertal virilization
Gynecomastia in puberty
male infertility

Question 84

What is the inheritance of AIS? What is the molecular pathogenesis?

Answer 84

XLR
majority are missense variants that impair DNA or androgen binding and cause CAIS or PAIS; a small number have been proven to cause MAIS
nearly all SNVs in the androgen-binding domain impair androgen binding and impair transactivation by the AR (LOF)

Question 85

Describe the underlying genetic mechanism of 5-alpha reductase deficiency

Answer 85

converts testosterone to more potent dihydrotestosterone
testosterone: driver for development of the genitalia and Wolffian duct
DHT: role in the genesis of male external genitalia
PV in SRD5A2 causes decreased production of DHT during fetal development, and this leads to defective external genital development and ambiguous genitalia

Question 86

What is the genotype of individuals w 5-alpha reductase deficiency (typically)

Answer 86

46,XY

Question 87

What are the features associated w 5-alpha reductase deficiency

Answer 87

AR
Newborns might have genitalia resembling labia majora, which would be unfused labioscrotal folds; phallus may look more like a clitoris
internal genitalia include seminal vesicles, epididymis, vas deferens, and ejaculatory duct, and you may not see any Mullerian structures
tend to be raised as females until puberty, when they start having virilization
development of secondary sex characteristics during puberty does not need the presence of DHT, ONLY testosterone
infertile

Question 88

What testing should be done for 5-alpha reductase deficiency

Answer 88

can do a biochemical assay which children show an increase in the ratio of testosterone to DHT after bhCG administration (not recommended since a good # of false negatives)
sequencing and del dup of SRD5A2

Question 89

What is the recommended tx/management for 5-alpha reductase deficiency

Answer 89

testes must be removed before child attains puberty and virilization
developmental size of phallus at time of dx and its ability to develop into a functional component is the main criteria of consideration before raising the child as male

Question 90

What features are associated w Y chromosome infertility and how is it dx

Answer 90

characterized by azoospermia or severe, moderate, mild oligospermia
males w Y chrom infertility usually have no obvious symptoms, although physical exam may reveal small testes

established in a males w characteristic clinical and lab findings and identification of a hemizygous del of Yq involving the AZF regions/ identification of a heterozygous PV in USP9Y

Question 91

When is IVF/ICSI successful in those w Y chromosome infertility

Answer 91

for males w AZFc dels (but not those w AZFb and AZFa dels)

Question 92

Describe the clinical features associated w Kallman syndrome

Answer 92

congenital form of hypogonadotropic hypogonadism; deficit of GnRH hormone results in decreased levels of sex steroids leading to a lack of sexual maturity and the absence of secondary sexual characteristics
increased risk of developing osteoporosis, lack of testicular development, failure to start menstruation in women, lack of pubic hair and underdeveloped breasts due to low levels of LH and FSH
anosmia/hyposmia, cleft palate and lip, cleft hand or foot, hypodontia, unilateral renal agenesis, central hearing impairment, mirror movements of hands (synkinesis), ataxia

Question 93

What is the genetic cause of Kallman syndrome

Answer 93

dx usually occurs when child fails to begin puberty
PV in ANOS1/FGFR1
often X-linked, can also be AR

Question 94

What is the tx for Kallman syndrome

Answer 94

usually tx pharmacologically w steroid replacement therapy such as testosterone or estrogen-progestin supplementation
fertility increased using gonadotropin-based pharmacologic options
complications can include osteoporosis, cardiac dz, and psychological/neuro disorders

Question 95

What are the clinical features associated w Van der Woude

Answer 95

have ONE or more of the following anomalies:
congenital (usually bilateral) paramedian lower lip fistulae (pits) or sometimes small mounds w a sinus tract leading from a mucous gland of the lip
cleft lip
cleft palate
submucous cleft palate
growth and intelligence are typical

Question 96

How is the dx of Van der Woude established

Answer 96

dx is established in a proband w suggestive findings and a heterozygous PV in IRF6 identified by molecular testing (PV identified in ~72% of individuals w VWS phenotype)
AD
whole gene dels and nearly all protein truncation variants cause a VWS phenotype
haploinsufficiency causes phenotype

Question 97

What are the tx recommendations for Van der Woude

Answer 97

sx tx of lip pits and cleft lip and palate pediatric dentistry, orthodontia, speech therapy, feeding therapy
orofacial clefts are tx in a standard manner

Question 98

Describe the clinical features associated w Treacher Collins syndrome

Answer 98

Treacher Collins syndrome (TCS) is characterized by lower eyelid abnormalities, malar hypoplasia, downslanted palpebral fissures, and micro- or retrognathia due to symmetric hypoplasia of the zygomatic bones, maxilla, and mandible. External ear anomalies (absent, small, malformed, and/or posteriorly rotated ears and atresia or stenosis of the external auditory canals)
40-50% w conductive hearing loss most commonly due to malformation of the ossicles and hypoplasia of the middle ear cavities (inner ear is normal)
significant respiratory and feeding difficulties in infancy
CP, unilateral/bilateral choanal stenosis or atresia

choanal atresia/stenosis or severe micrognathia w glossoptosis can obstruct can obstruct the airway in an infant from the time of delivery
ASD, VSD, PDA, patent foramen ovale

Question 99

How is the molecular and clinical dx of Treacher Collins established

Answer 99

heterozygous pathogenic variant in TCOF1, POLR1D, or POLR1B, biallelic pathogenic variants in POLR1C, or, rarely, biallelic pathogenic variants in POLR1D identified by molecular genetic testing; can also be 5q32-q33.1

clinical diagnosis of TCS can be established in a proband with characteristic bilaterally symmetric abnormalities of the facial and mandibular structures, including downslanted palpebral fissures, hypoplasia of the zygomatic complex and mandible, and conductive hearing loss

Question 100

What are the tx recommendations for someone w Treacher Collins

Answer 100

Treatment should be tailored to the specific needs of each individual, preferably by a multidisciplinary craniofacial management team. Neonates with airway issues may require airway management at delivery, special positioning, or tracheostomy to facilitate ventilation. Tube feeding may be needed for adequate caloric intake. Cleft palate repair (if needed) occurs at about age one year. Hearing loss is treated with bone conduction amplification, speech therapy, and educational intervention. Management of ocular issues is per ophthalmologist. Standard management for cardiac, gastrointestinal, renal, and limb anomalies. Craniofacial reconstruction is often necessary: zygomatic and orbital reconstruction at about age five to seven years, and bilateral microtia and/or narrow ear canal reconstruction after age six years. Botulinum toxin and subsequent surgery for coloboma of the lower eyelid. Eyelid reconstruction as needed for downslanted palpebral fissures. Orthodonture for misaligned teeth. The age of maxillomandibular reconstruction varies by severity; orthognathic therapies are typically before age 16 years

Question 101

What is the de novo rate seen in Treacher Collins

Answer 101

55-61% de novo
significant intrafamilial clinical variability is common

Question 102

What prenatal features on u/s would be consistent w Treacher Collins

Answer 102

polyhydramnios, microcephaly, abnormal fetal facial features (micrognathia), and abnormal fetal swallowing

Question 103

What is the molecular pathogenesis of Treacher Collins

Answer 103

cartilage and bone making up the craniofacial complex is primarily derived from neural crest cells; insufficient # of mature ribosomes in the neuroepithelium and neural crest cells during embryogenesis
LOF

Question 104

What are the features of Goldenhar syndrome

Answer 104

congenital disorder of craniofacial morphogenesis, phenotypic continuum
malformations of structures derived from the first and second branchial arches, including eyes, mouth (lips, tongue, and palate), ear, maxilla, and mandible, microtia, facial asymmetry (right sided favored), and epibulbar dermoid or lipodermoid, DD, auricular abnormalities like microtia, hemifacial microsomia, preauricular tags, appendages and fistula
males more common than females to be affected (3:2)
normal life span and intelligence

Question 105

What is the molecular pathogenesis of Goldenhar syndrome

Answer 105

dx is mainly clinical, no specific genetic tests for dx
FH in 2-12% of cases, 2-3% risk to the first degree relatives of an affected individual
AD and AR among familial cases

Question 106

What are the triad of features most commonly associated w Goldenhar syndrome

Answer 106

mandibular hypoplasia w facial asymmetry, oculo-auricular malformations, and vertebral abnormalities

Question 107

What features on prenatal u/s are consistent w the dx of Goldenhar syndrome

Answer 107

microtia, preauricular tags, mandibular hypoplasia, microphthalmia, orbital hypoplasia

Question 108

What is the recommended tx for Goldenhar syndrome

Answer 108

should be seen w: pediatrician, ophthalmologist, oral maxillofacial sx, audiologist, otolaryngologist, speech language pathologist, orthodontist, plastic sx, radiologist, neurosx, social worker, and psychologist
upper eyelid coloboma is a sx emergency which depends on size, location, and general state of the child
management of dermoid depends upon the grade and extent of the lesion; management w spectacles unless poor vision or noncompliance w spectacles in which sx would be needed

Question 109

What are the clinical features associated w branchiootorenal spectrum disorder

Answer 109

Branchiootorenal spectrum disorder (BORSD) is characterized by malformations of the outer, middle, and inner ear associated with conductive, sensorineural, or mixed hearing impairment, branchial fistulae and cysts, and renal malformations ranging from mild renal hypoplasia to bilateral renal agenesis. Some individuals progress to end-stage renal disease (ESRD) later in life.

Extreme variability

Question 110

How is the molecular dx of branchiootorenal spectrum disorder established

Answer 110

diagnosis of branchiootorenal spectrum disorder is based on clinical criteria
and/or heterozygous pathogenic variants in EYA1, SIX1, or SIX5 w multigene panel
AD

Question 111

What are the tx recommendations for branchiootorenal spectrum disorder

Answer 111

Excision of branchial cleft cysts/fistulae, fitting with appropriate aural habilitation, and enrollment in appropriate educational programs for the hearing impaired are appropriate. A canaloplasty should be considered to correct an atretic external auditory canal. Medical and surgical treatment for vesicoureteral reflux may prevent progression to end-stage renal disease (ESRD). ESRD may require renal transplantation.

Question 112

How is the clinical dx of branchiootorenal spectrum disorder

Answer 112

dx established w 2 major and 2 minor OR 1 major and 3 minor
major
second branchial arch anomalies
deafness
preauricular pits
auricular malformation
renal anomalies

minor
external auditory canal anomalies
middle ear anomalies
inner ear anomalies
preauricular tags
facial asymmetry, palate abnormalities

Question 113

What is the de novo rate for branchiootorenal spectrum disorder

Answer 113

10%
90% have an affected parent

Question 114

What u/s findings are consistent w dx of branchiotorenal spectrum disorder

Answer 114

significant renal involvement and/or oligohydramnios

Question 115

What are the clinical features associated w Gorlin syndrome

Answer 115

development of multiple jaw keratocysts, frequently beginning in the second decade of life, and/or basal cell carcinomas (BCCs), usually from the third decade onward; recognizable appearance with macrocephaly, frontal bossing, coarse facial features, and facial milia.
have skeletal anomalies (e.g., bifid ribs, wedge-shaped vertebrae). Ectopic calcification, particularly in the falx by 30yo
Cardiac and ovarian fibromas occur in approximately 2% and 20%
5% of children develop medulloblastoma (primitive neuroectodermal tumor);
risk of developing medulloblastoma is substantially higher in individuals with an SUFU pathogenic variant (33%) than in those with a PTCH1 pathogenic variant (<2%). Peak incidence is at age one to two years

Question 116

How is the dx of Gorlin syndrome established

Answer 116

The diagnosis of NBCCS is established in a proband who fulfills proposed diagnostic clinical criteria. Identification of a heterozygous germline pathogenic variant in PTCH1 or SUFU by molecular genetic testing establishes the diagnosis if clinical features are inconclusive

Question 117

What are the tx recommendations for Gorlin syndrome pts

Answer 117

Best provided by specialists experienced with the condition; avoidance of direct sun exposure through the use of complete sunblock and covering of exposed skin with long sleeves, high collars, and hats; early treatment of BCCs to ensure complete eradication of aggressive BCCs and to preserve normal tissue to prevent disfigurement; sonic hedgehog inhibitors such as vismodegib to treat severe BCCs; jaw keratocysts usually require surgical excision; treatment of medulloblastoma per neurosurgeon/oncologist.

Question 118

What is the de novo rate of Gorlin syndrome

Answer 118

20-30%

Question 119

What are the major and minor criteria that can give a pt the dx of Gorlin syndrome

Answer 119

need 2 major and 1 minor
MAJOR
Lamellar (sheet-like) calcification of the falx
Jaw keratocyst
Palmar/plantar pits (≥2)
Multiple basal cell carcinomas (BCCs) (>5 in a lifetime)
First degree relative w dx of BCCS

MINOR
childhood medulloblastoma
lymphomesenteric or pleural cysts
macrocephaly
CL/CP
Rib/vertebral anomalies
preaxial or postaxial polydactyly
ovarian/cardiac fibromas
ocular anomalies

Question 120

What is the dz mechanism for Gorlin syndrome

Answer 120

PTCH1 functions as a tumor suppressor
SUFU acts as a negative regulator

LOF

Question 121

What are the clinical features of Apert syndrome

Answer 121

presence of multisuture craniosynostosis, midface retrusion, and syndactyly of the hands with fusion of the second through fourth nails
coronal craniosynostosis, and a majority also have involvement of the sagittal and lambdoid sutures; midface retrusion, cleft palate in some
Feeding issues, dental abnormalities, hearing loss, hyperhidrosis, and progressive synostosis of multiple bones (skull, hands, feet, carpus, tarsus, and cervical vertebrae)
multilevel airway obstruction due to narrowing of the nasal passages or tracheal anomalies
nonprogressive ventriculomegaly, normal intelligence or mild ID
vertebral fusions (C5-C6), hyperhidrosis, acne, nail dystrophy

Question 122

How is the dx of Apert syndrome established

Answer 122

in a proband with classic clinical characteristics (multisuture craniosynostosis, midface retrusion, and syndactyly) and/or by the identification of a heterozygous pathogenic variant in FGFR2 by molecular genetic testing AND phenotypic features consistent with Apert syndrome.
exon or whole gene del/dups are not detected

Question 123

What is the craniosynostosis associated w Apert syndrome

Answer 123

coronal w most having sagittal and lamboid sutures

Question 124

What are the tx recommendations for pts w Apert syndrome

Answer 124

Management by a craniofacial team is ideal. In general, multisutural craniosynostosis should be surgically repaired in the first year of life; jaw surgery to advance the midface often occurs in childhood and adolescence. Cleft palate repair may be performed prior to the development of pressure consonants. Feeding therapy is often helpful. Pediatric dental care is recommended. Treatment of strabismus should be performed by an ophthalmologist with expertise in eye alignment in children with craniosynostosis. Hearing aids may be required for hearing loss. If airway obstruction is present, temporizing measures may be required. Treatment of sleep apnea by surgical intervention and/or supplemental oxygen via nasal cannula may be required. The type and timing of surgical repair for syndactyly depends on the presence of thumb syndactyly and extent of soft tissue deficiency. Early intervention services for speech abnormalities and developmental delay should be initiated. Standard treatment of congenital heart defects, malrotation, cryptorchidism in males, hydronephrosis, acne, and scoliosis should be instituted when appropriate.

Question 125

What is the de novo rate of Apert

Answer 125

most have the disorder as a de novo condition in FGFR2
APA

Question 126

Describe the dz mechanism for Apert

Answer 126

GOF in FGFR2
recurrent and common variants p.Ser252Trp, p.Pro253Arg, and p.Ser252Phe in the 5’ end of exon 7

Question 127

What are the clinical features associated w Crouzon syndrome

Answer 127

normal headshape to cloverleaf skull, may have normal features at birth w craniofacial features developing over the first yr or two of life including: significant proptosis, external strabismus, midface retrusion, convex nasal ridge, and relative prognathism
high arched palate is common
hearing loss in 74% and is most often conductive
variable from no airway issues
normal extremities
Chiari I malformation, progressive hydrocephalus; most individuals have normal intelligence; 25% have vertebral fusion, most often C2-C3

Question 128

What are the clinical features associated w Pfeiffer syndrome

Answer 128

multisuture craniosynostosis ranging from normal head shape to cloverleaf skull
midface retrusion is moderate to severe; eyes are very prominent and there is a risk for subluxation of the globe
hearing loss in 92% due to stenosis or atresia of the external auditory canal
some have multilevel airway obstruction
thumbs and great toes are broad and medially deviated; synostosis of the radius and humerus, sacral appendages
intelligence ranges from normal to severe ID; seizures and an increased risk for early death
28% of children need sx for hydrocephalus; 50% w cloverleaf skull have Chiari I malformation

Question 129

What are the clinical features associated w Greig cephalopolysyndactyly syndrome

Answer 129

AD
Macrocephaly, frontal bossing, hypertelorism, wide nasal bridge
polydactyly of the hands (often postaxial) and feet w syndactyly of toes 1-3 and often a duplicated hallux

Question 130

What are the clinical features associated w Shprintzen-Goldberg syndrome

Answer 130

AD
Coronal, sagittal, or lambdoid craniosynostosis
tall or prominent forehead, proptosis, hypertelorism, downslanted palpebral fissures, malar flattening
hands: arachnodactyly; campodactyly
feet: malposition, pes planus

Question 131

Describe the clinical features associated w Saethre Chotzen syndrome

Answer 131

characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), strabismus, ptosis, and characteristic appearance of the ear (small pinna with a prominent superior and/or inferior crus)
CRANIOSYNOSTOSIS IS NOT AN OBLIGATORY FINDING
Syndactyly of digits two and three of the hand is variably present. Cognitive development is usually normal
hypertelorism, palatal anomalies, obstructive sleep apnea, increased intracranial pressure, short stature, and congenital heart malformations.

Question 132

How is the dx of Saethre Chotzen syndrome established

Answer 132

diagnosis of SCS is established in a proband with typical clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in TWIST1 identified by molecular genetic testing.
AD; many dz w SCS have an affected parent

Question 133

What are the tx recommendations for Saethre Chotzen

Answer 133

Ongoing management by an established craniofacial team which may include cranioplasty in the first year of life and midface surgery in childhood as needed for dental malocclusion, swallowing difficulties, and respiratory problems. If a cleft palate is present, surgical repair usually follows cranioplasty. As needed: orthodontic treatment and/or orthognathic surgery at the completion of facial growth; developmental intervention; routine treatment of hearing loss; ophthalmologic evaluation and, if ptosis is present, intervention to prevent amblyopia, with surgical repair during early childhood as needed.

Question 134

What testing should be ordered for dx of Saethre Chotzen

Answer 134

single gene testing for TWIST1
CMA (risk for DD w large dels involving TWIST1 is ~90%, or 8x > than w intragenic PVs)
karyotype can be considered if dx is strongly suspected w neg results since rearrangements have been reported

Question 135

What is the molecular pathogenesis of Saethre Chotzen

Answer 135

LOF, functional haploinsufficiency of Twist related protein 1

Question 136

What are the clinical features associated w Carpenter syndrome

Answer 136

macrosomia, umbilical hernia, and craniosynostosis (cloverleaf configuration to predominant involvement of the metopic ridge to craniofacial asymmetry) at birth
raised intracranial pressure, difficulty in articulation, frequent ear infections w resultant hearing loss; brachydactyly, cutaneous syndactyly, preaxial polydactyly in the toes w postaxial polydactyly in the hands w broad thumbs and absent middle phalanges

cardiac malformations: VSD, PDA, pulmonic stenosis, tetralogy of Fallot, and transposition of the great vessels; ID is common, hypogonadism, cryptorchidism, small primary dentition, teeth are short, undersized, and widely spaced, prolonged retention of the primary teeth
growth is slightly delayed/normal w short stature, persistent obesity in childhood, deformed hips, kyphoscoliosis, and genu valgum

Question 137

What is the etiology of Carpenter syndrome

Answer 137

truncating, missense, and LOF in RAB23 and less commonly MEGF8 (AR)
defective lateralization and less severe craniosynostosis

Question 138

What on u/s can be suggestive of Carpenter syndrome

Answer 138

abnormal head shape, short and bowed femurs, flattened face, proptosis, heart defect, heterotaxy, and digit anomalies

Question 139

What is the recommended tx for Carpenter syndrome? Prognosis?

Answer 139

craniofacial reconstruction to improve appearance and prevent ID
Sx for CHDs and shunting may be required if there is raised intercranial pressure

prognosis is highly variable depending on the severity of the malformations and the degree of ID; life expectancy is shortened, mainly due to heart defects